From Metchnikoff to Microbiota: the fame of probiotic bacteria

Guiseppe Arcimboldo "Vertumnus", c. 1590-1

Useful properties of probiotics were observed more than one hundred years ago, but the real expansion in the science of probiotics happened only recently. Growing number of studies show that probiotics not only interact with other microorganisms that live within the body, but also with the human body itself. The question arises – if we understand the detailed mechanisms of how probiotics work, can we use them as therapeutics?

In the first and second decade of the 20th century, immunologist and Nobel Prize winner Ilya Ilyich (Élie) Metchnikoff became interested in studying means of increasing human longevity. His attention was drawn to the residents of the Balkan States and Russia, who seemed to have among them an unusually high proportion of centenarians. He attributed these people’s longevity to the very humble and simple lifestyle. Following their diet as an example, he recommended daily intake of probiotics in the form of “soured milk” (yogurt) prepared by addition of lactic bacteria, or of pure cultures of the “Bulgarian bacillus” (Lactobacillus bulgaricus), together with “a certain quantity of milk, sugar, or sucrose” (1).

Albeit Metchnikoff’s fame with his pioneering work in immunology, the probiotic theory was somewhat left aside for a time. In the 1990s, with the rise in antibiotic resistance, probiotics returned to the scientific focus as a potential alternative to antibiotic therapy. Our current view on probiotics is summarized by the World Health Organization definition, which says that probiotics are “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host”. The biggest probiotic group are the lactic acid bacteria such as lactobacilli; another large group are bifidobacteria, but some are members of Saccharomyces (yeast) genus, or even belong to Escherichia coli species.

Nowadays, probiotics are easily available in yogurt and other fermented drinks, capsules, or powder. Their use is often paired with the use of prebiotics, food ingredients that promote the growth or activity of beneficial bacteria. In their chemical nature, prebiotics are complex chains that consist of sugar units such as glucose, galactose, fructose and lactose. Over the last years, evidence of usefulness of probiotics accumulated, mainly thanks to numerous clinical studies that measured the effect of probiotics on individuals with a health condition (note that usually these studies determine if probiotics are effective in ameliorating a condition, but don’t explain the mechanism of action). For example, Lactobacillus reuteri DSM 17938 are shown to help in antibiotic caused diarrhoea, and in fighting the bacterial causes of ulcer (2,3). Some strains of Lactobacillus rhamnosus and helveticus isolated form dairy products are known to be important in dermatitis treatment (4). Saccharomyces boulardii is particularly helpful in diarrhoea in children, and Escherichia coli strains in ulcerative colitis cases (5,6).

So, probiotics (and prebiotics) were around us and in our food for a long time, and we have some evidence that they are beneficial, but – how do they work?

How do probiotics work?

In 2008, the Human Microbiome project was launched, aiming to identify and characterize the microbial species found in healthy and non-healthy humans. As a result of this project, several thousands of species were found to live in and on the human body. Each of our bodies carries about 10ˆ14 microbes, which colonize organs such as the skin, mouth, gut, and urogenital tract. The “microbial composition” of each one of us is influenced by several factors: our genetic background, age, diet, stress, etc. In each of the mentioned organs, microbial populations may exist in a healthy equilibrium state (eubiosis); however, in the case of perturbations such as an infection or antibiotic treatment, the healthy equilibrium state is interrupted and dysbiosis occurs (note that the terms “eubiosis” and “dysbiosis” were coined long before Metchnikoff, who had also used them). Generally, probiotics are considered to help the microbial community to return to the healthy equilibrium state. It is important to point out that the effects of probiotics on our health are species- and organ-specific, meaning that not all probiotics act beneficially in any surrounding they find themselves in.

The human microbiome project showed that an unexpectedly high microbial diversity existed in human mouth. Regular tooth brushing disrupts the microbial community, and some foods, especially simple sugars, increase growth of unwanted pathogenic bacteria. Even so, the healthy equilibrium may be kept for a long time in the oral cavity, probably because of the local non-pathogenic bacteria that produce molecules which prevent harmful bacteria to attach to different surfaces in the mouth (Fig 1), (7). So, do probiotics have any role in oral cavity health?

Some studies show that daily intake of probiotic lactobacilli could help to reduce the formation of caries through a mechanism that is thought to be competitive exclusion. This simply means that probiotics occupy surface and don’t allow harmful bacteria to attach (Fig 1). It is known that probiotics can push out the pathogenic staphylococci and streptococci in the mouth (7). These promising results received attention from clinicians and dentists; research is now underway to determine if our dentists should really recommend taking probiotics daily.

Figure 1. Mechanisms that help to preserve the healthy microbial communities in human mouth: Beneficial bacteria keep the bad guys out by production of “slippery” molecules (left). Probiotics can also block the adhesion of the harmful bacteria by competing for adhesion sites (right). Taken with permission from (7).

Another great human body example is the gut. The gut is certainly the human organ with the highest microbial diversity. Intestinal epithelial cells are the main interface between the microbes in the lumen (the interior of the intestine) and the immune system cells in the underlying intestinal tissue. Epithelial cells are tightly connected to each other to make a layer and protect the underlying tissue. If eubiosis state is perturbed (our gut microbiota becomes different from the “normal” state), and the epithelial cell barrier is compromised, this may lead to chronic inflammation. Chronic inflammation is one of the key steps in the development of serious conditions such as ulcerative colitis and Crohn’s disease.

In this case, some strains and probiotic mixtures were shown to be helpful in the treatment and prevention of bowel diseases. Probiotics may decrease the death of cells in the epithelial layer barrier and/or can make the inter-cellular connections tighter (Fig 2). Some probiotic strains are able to induce production of protective chemicals that impermeabilize cells of intestinal epithelial layer from harmful bacteria (Fig 2). Finally, probiotics were also shown to be able to manipulate different parts of the human immune system, which resulted in lower production of inflammation factors in the gut. All these mechanisms together may contribute to the known usefulness of probiotics, such as the proven case of Escherichia coli Nissle in promoting the remission of ulcerative colitis (6).

Figure 2. Mechanisms that help to preserve a healthy state in human microbial communities in the gut: Probiotics are able to make cell-to-cell connections in the gut stronger (left); by doing that they prevent harmful bacteria from getting into the touch with our immune system and causing infection and inflammation. Additionally, probiotics can produce protective chemicals that recognize harmful bacteria and help to eliminate them. Finally, they can also help our immune system to reduce inflammation caused by the harmful bacteria. Taken with permission from (7).

Finally, we focus on a new exciting field that investigates the interaction between the gut microbiota and the nervous system, the famous gut-brain axis. This “axis” consists of gut, enteric nervous system (a complex part of the peripheral nervous system that is almost independent of the central nervous system and innervates most of the digestive tract), and the brain. In a pivotal study (8), it was shown that mice raised in sterile conditions, and therefore lacking any microbiota including those in the gut, showed exaggerated physiological reactions to stress when compared to those raised in their normal environment. Moreover, when “sterile” mice were colonized by probiotic lactobacteria, their reactions to stress became similar to those of mice grown in non-sterile conditions, revealing the very important role of the gut-brain axis in behaviour.

However, deciphering the role of probiotics in the gut-brain axis is a far more complex process. In addition to the complex functioning of the brain, the function of the immune and the endocrine systems have now also to be taken into consideration in this process. Nevertheless, much needed attention is now being given to the brain-wide effects of products that arise from the microbial metabolism of molecules available in the gut. In the end, you are what you eat, some would say.

Researchers in this new field are very enthusiastic about its future. They have even come up with a term, “psychobiotics”, defined as “probiotics which, when ingested, confer mental health benefits through interactions with commensal gut bacteria”. They have also added prebiotics to this definition.

Remember the story about Metchnikoff? We may now close the circle by returning to his late works, in which, one hundred years ago, he advocated the consumption of microbes that we would today probably call probiotics, together with sugars such as glucose, sucrose, and milk. The latter is rich in lactose and oligosaccharides, which are now seen as prebiotics too. Metchnikoff, through careful observations, managed to reach conclusions which are now being re-discovered by modern science while looking at the specific mechanisms. The science of probiotics, backed by the Human Microbiome project, is becoming a field with exciting findings which will provide us new views of how the human organism functions in health and disease.

References:

Mackowiak PA (2013) Recycling Metchnikoff: Probiotics, the Intestinal Microbiome and the Quest for Long Life. Front Public Health 1:52.